Uveal Melanoma (UM) is the most common form of primary eye cancer and is associated with very poor prognosis and morbidity. UM often metastasizes, primarily to the liver and metastatic tumors are uniformly fatal. Gene profiling of tumors has allowed subdividing UMs into Low Metastatic risk (Class 1) and High Metastatic risk (Class 2) variants however, until recently, the genetic basis for this metastatic propensity was unclear. In late November of 2010, Harbour et al. reported that the tumor suppressor gene, BAP1 is mutated in 84% of Class 1 metastatic tumors. BAP1 directly controls the metastatic phenotype of UM as shown by ablation of wild type BAP1 expression. Nothing is known of the mechanism by which BAP1 controls the metastatic phenotype in UM. BAP1 was originally discovered in 1998 by the Rauscher Laboratory We showed that it possessed tumor suppressor activity and catalyzes ubiquitin hydrolysis. Recent work has shown that BAP1 participates in gene regulation by participating in multi-protein complexes which control cell differentiation and development. Thus, BAP1 likely controls the metastatic phenotype via epigenetic mediated gene regulation. In this proposal we will provide a mechanistic basis for the control of metastasis in UM by connecting the biological and transcriptional roles of BAP1 in in vitro and animal models of UM by performing the following specific aims: 1) Define the role of BAP1 in metastasis of uveal melanoma using cell culture and animal models. 2) Identify the spectrum of genes influenced by BAP1 during establishment and maintenance of the metastatic phenotype. 3) Identify Promoters which are directly targeted in chromatin by the BAP1-containing polycomb complex. 4) Define the composition and functions of the BAP1 multiprotein complex in UM cells and its role in gene regulation, ubiquitin hydrolysis and biologic functions of BAP1. These experiments will provide a mechanistic basis for metastasis suppression by BAP1 and validate it as a key target for controlling the pathogenesis of Uveal Melanoma. PUBLIC HEALTH RELEVANCE: Uveal Melanoma is the most common form of primary ocular tumor. Despite advances in early detection and treatment, there is high mortality in patients with metastatic spread. We propose to define the function of a new gene which plays a causal role in the process of metastasis. This analysis should provide new targets and therapeutic strategies for Uveal Melanoma. The proposal is highly relevant to furthering public health.